NETTER-2 Trial Shows Lutathera® as First-Line Treatment Significantly Reduces Disease Progression or Death

Lutathera®, when given with long-acting release octreotide, reduces the risk of disease progression or death in those with newly diagnosed Grade 2 and 3 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to the results of the NETTER-2 clinical trial. The trial is the first positive Phase 3 study for a radioligand therapy in a first-line setting (i.e., as a first treatment option).

Novartis presented the results of the study at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium on January 19, 2024.

Lutathera is a peptide receptor radionuclide therapy (PRRT) that selectively targets the somatostatin receptor (SSTR) found on NET cells and delivers radiation specifically to the cancer cells. Radioligand therapy aims to harness the power of radioactive atoms to deliver targeted treatment to cells anywhere in the body.

Based on the results of the NETTER-1 trial, the U.S. Food and Drug Administration approved Lutathera in January 2018 to treat adults with SSTR-positive GEP-NETs. The NETTER-1 trial focused on Grade 1 and 2 midgut NETs, while the NETTER-2 trial enrolled Grade 2 and 3 GEP-NETs.

“The significance of this trial is that it offers a potential new option for previously untreated patients with grade 2/3 well-differentiated neuroendocrine tumors,” said Mark Lewis, MD, director of Gastrointestinal Oncology at Intermountain Healthcare in Salt Lake City and a member of the NETRF Board of Directors. “However, its numbering as NETTER-2 somewhat misleadingly positions it as a direct sequel to NETTER-1 when it is not, as the patient populations under investigation are very different between the two trials.”

The randomized, multicenter NETTER-2 trial compared Lutathera plus long-acting octreotide to treatment with high-dose, long-acting octreotide alone as a first-line treatment. During the trial, Lutathera plus long-acting octreotide significantly extended median progression-free survival (PFS) of study participants to 22.8 months compared to 8.5 months with octreotide alone.

No new or unexpected safety findings were observed in the study, and data are consistent with Lutathera’s established safety profile, according to Novartis. Most participants in the Lutathera arm of the trial (88%) received all four cycles of treatment. The most common side effects observed in the Lutathera plus octreotide group compared to those treated with octreotide alone included nausea, diarrhea, abdominal pain, and a decrease in a type of white blood cells called lymphocytes.

Dr. Lewis noted that while the primary PFS endpoint was impressively met in the NETTER-2 trial, PFS does not necessarily extend to longer overall survival, especially if participants on the control arm of high-dose octreotide are able to crossover and also receive PRRT. He added that while the safety profile from the trial looks appealing, a fear of any treating oncologist who administers PRRT is damage to the bone marrow.

With respect to whether this treatment approach will soon be available to patients, Dr. Lewis noted that there can be a wide gulf between the announcement of a study’s results and the ability of physicians to act on it for their patients.

“I think that even if oncologists believe NETTER-2 moves PRRT to the first line for some patients, the rate-limiting step to acting upon that decision will occur at the level of insurance coverage, especially for such an expensive treatment that is yet to show an advantage in overall survival,” he said.

The NETTER-2 trial continues to further evaluate secondary endpoints, including overall survival and long-term safety.